Progressive pancreatic carcinoma and cholangioma are known for their extreme difficulties in diagnosis and treatment and as so-called intractable cancers. In other words, because the pancreas and bile duct are surrounded by other organs such as the stomach, duodenum, small intestine, large intestine, liver, gall bladder, spleen, etc., it is difficult to detect cancer, and also manifestations that are characteristic to cancer are not found in the early stages. Therefore, early detection is difficult, and when it is diagnosed as a carcinoma, it is often too late to treat it.
On the other hand, there is obstructive jaundice (a symptom of the body turning yellow), which is a symptom related in some degree to these carcinomas. This is caused when the bile duct at the head of the pancreas that runs from the liver to the duodenum (that is, a pipe that drains bile created in the liver to the alimentary canal) is obstructed by a carcinoma, stopping the discharging of the bile. Generally, the first step of treating a progressive pancreatic carcinoma/bile duct cancer is to improve this obstructive jaundice.
As a means to improve this obstructive jaundice, a biliary stent is used. This biliary stent is a plastic or metal tubular (stent), that allows the bile to drain by enlarging the section of the bile duct that became narrow, by being placed into the bile duct via the duodenal papilla like an endoscope.
However, because the bile drainage of this biliary stent is exposed to the duodenum, duodenal juice flows back into the stent lumen. As a result, various kinds of Enterobacteriacae (Escherichia coli bacteria, etc.) present in the duodenal juice adhere to the surface of the stent lumen, where they multiply, and form so-called biofilm by producing exobacterial materials (polysaccharide) to build a complex three-dimensional structure. Once a biofilm is formed, on its surface, gallstones (calcium bilirubinate is the main component, and the enzymes produced by the bacteria and free radicals that accompany infection contribute to formation) are deposited, which in turn closes the stent lumen.
Because of this biofilm formation, the biliary stent lumen is blocked 3 months after operation. Thus it needs to be replaced with a new biliary stent. However, because the life expectancy, for example, of a pancreatic carcinoma patient, is only about 6 months, repeated operations lessen the quality of life for the patient as well as creating a large economic burden.
Moreover, a biofilm formed on a biological surface may cause infectious diseases such as chronic bronchitis and chronic osteomyelitis. Also, when a biofilm is formed on a prosthetic substrate surface, such as prosthetic heart valve, prosthetic joint, and urethral catheter, etc., sepsis may accompany it, and in the worse case may lead to death.
Currently, in order to prevent biofilm formation in biliary stents, various antibiotics (local administration, blood administration are used (Is prophylactic ciprofloxacin effective in delaying biliary stent blockage?, Gastrointest Endosc 52:175-182). However, long-term administration of antibiotics has a high probability of causing antibiotic-resistant bacteria to emerge. Thus the period of administration is at most one week. Once a biofilm is formed, it shows strong resistance to drugs. Thus currently there is no effective drug for it.
Moreover, in order to suppress bacterial adhesion to stent surfaces, biliary stents with a coating of a highly hydrophilic surface polymer (Product name: Hydromer) and stents formed by fluoropolymers (PFA; perfluoroalkoxy PTFE) which is reported to have little adhesion with animal cells, have also been developed. However, these materials cannot suppress bacterial growth. Therefore, if a small amount of bacteria with a high proliferating ability (the doubling time of the E. coli is 30 minutes) adheres on their surfaces, they cannot prevent the bacteria's growth, and thus they are unable to inhibit biofilm formation.
Also, in order to suppress bacterial growth, drug-eluting polymers using antibiotic and silver ion have been developed, which showed effectiveness at the experimental level. However, toxicity and effects on the living body pose problems, Thus, they have not been put to practical use for the human body.
As mentioned above, conventionally, the administering of antibiotics and the coating of a fluoropolymer have been used in order to prevent biofilm formation on the biliary stent lumen. However, neither of them is practical in terms of efficacy and safety.